Journal article
Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells
Cell death discovery, Vol.9(1), 451
12/12/2023
DOI: 10.1038/s41420-023-01738-x
PMCID: PMC10716181
PMID: 38086808
Abstract
Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death. One tumor type that exhibits a shift in the sphingolipid balance towards S1P is glioblastoma (GBM), a highly aggressive brain tumor. GBMs almost always recur despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Understanding sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target dysregulation of sphingolipid metabolism in GBM. Carmofur, a derivative of 5-fluorouracil, inhibits acid ceramidase (ASAH1), a key enzyme in the production of S1P, and is in use outside the USA to treat colorectal cancer. We find that the mRNA for ASAH1, but not other ceramidases, is elevated in recurrent GBM. When TMZ-resistant GBM cells were treated with carmofur, decreased cell growth and increased apoptosis were observed along with cell cycle perturbations. RNA-sequencing identified decreases in cell cycle control pathways that were specific to TMZ-resistant cells. Furthermore, the transcription factor and G1 to S phase regulator, E2F8, was upregulated in TMZ-resistant versus parental GBM cells and inhibited by carmofur treatment in TMZ-resistant GBM cells, specifically. These data suggest a possible role for E2F8 as a mediator of carmofur effects in the context of TMZ resistance. These data suggest the potential utility of normalizing the sphingolipid balance in the context of recurrent GBM.
Details
- Title: Subtitle
- Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells
- Creators
- Cyntanna C Hawkins - University of Alabama at BirminghamAmber B Jones - University of Alabama at BirminghamEmily R Gordon - HudsonAlpha Institute for BiotechnologyYuvika Harsh - University of Alabama at BirminghamJulia K Ziebro - University of Alabama at BirminghamChristopher D Willey - University of Alabama at BirminghamCorinne Griguer - University of IowaDavid K Crossman - University of Alabama at BirminghamSara J Cooper - HudsonAlpha Institute for BiotechnologySasanka Ramanadham - University of Alabama at BirminghamNinh Doan - New England Baptist HospitalAnita B Hjelmeland - University of Alabama at Birmingham
- Resource Type
- Journal article
- Publication Details
- Cell death discovery, Vol.9(1), 451
- DOI
- 10.1038/s41420-023-01738-x
- PMID
- 38086808
- PMCID
- PMC10716181
- NLM abbreviation
- Cell Death Discov
- ISSN
- 2058-7716
- eISSN
- 2058-7716
- Grant note
- F31 NS124130 / NINDS NIH HHS R01 NS104339 / NINDS NIH HHS R03 NS128449 / NINDS NIH HHS R01 DK110292 / NIDDK NIH HHS R21 AI169214 / NIAID NIH HHS P30 CA013148 / NCI NIH HHS
- Language
- English
- Date published
- 12/12/2023
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984530393902771
Metrics
10 Record Views